Ocular pharmacokinetic models of clonidine-3H hydrochloride.

A single topical instillation of clonidine-3H HCl solution (0.2%) was administered to the rabbit eye (30 microliter) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180 min. By 45-60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constant ka, 0.00139 min-1, aqueous humor elimination rate constant k10, 0.0658 min-1; mean residence time MRTd, 35.6 min; apparent steady-state volume of distribution Vss, 0.530 ml; and ocular clearance Qe, 14.9 microliter/min. The fraction absorbed from the single instillation is estimated as 0.0163.